Abstract

Polyamines are essential growth factors that have a positive role in cancer cell growth. Their metabolic pathway and the diverse enzymes involved have been studied in depth in multiple organisms and cells. Polyamine transport also contributes to the intracellular polyamine content but this is less well-studied in mammalian cells. As the polyamine transporters could provide a means of selective drug delivery to cancer cells, a greater understanding of polyamine transport and its regulation is needed. In this study, transport of polyamines and polyamine content was measured and the effect of modulating each was determined in human colorectal cancer cells. The results provide evidence that upregulation of polyamine transport depends on polyamine depletion and on the rate of cell growth. Polyamine transport occurred in all colorectal cancer cell lines tested but to varying extents. The cell lines with the lowest basal uptake showed the greatest increase in response to polyamine depletion. Kinetic parameters for putrescine and spermidine suggest the existence of two separate transporters. Transport was shown to be a saturable but non-polarised process that can be regulated both positively and negatively. Using the polyamine transporter to deliver anticancer drugs more selectively is now a reality, and the ability to manipulate the polyamine transport process increases the possibility of using these transporters therapeutically.

abstract = "Polyamines are essential growth factors that have a positive role in cancer cell growth. Their metabolic pathway and the diverse enzymes involved have been studied in depth in multiple organisms and cells. Polyamine transport also contributes to the intracellular polyamine content but this is less well-studied in mammalian cells. As the polyamine transporters could provide a means of selective drug delivery to cancer cells, a greater understanding of polyamine transport and its regulation is needed. In this study, transport of polyamines and polyamine content was measured and the effect of modulating each was determined in human colorectal cancer cells. The results provide evidence that upregulation of polyamine transport depends on polyamine depletion and on the rate of cell growth. Polyamine transport occurred in all colorectal cancer cell lines tested but to varying extents. The cell lines with the lowest basal uptake showed the greatest increase in response to polyamine depletion. Kinetic parameters for putrescine and spermidine suggest the existence of two separate transporters. Transport was shown to be a saturable but non-polarised process that can be regulated both positively and negatively. Using the polyamine transporter to deliver anticancer drugs more selectively is now a reality, and the ability to manipulate the polyamine transport process increases the possibility of using these transporters therapeutically.",

note = "Funding: M.C. was funded by CONACyT, Mexico with the PhD scholarship 237771/411030. Acknowledgments: We would like to thank Mark Burns of Aminex Therapeutics for kindly providing the AMXT compounds and P.M. Woster from Medical University of South Carolina for DFMO and Gary Cameron for LC-MS analyes Author Contributions: M.C. and H.M.W. designed the study. M.C. performed the experiments, interpreted the data and wrote the manuscript. H.M.W. interpreted the data and revised the manuscript. Conceptualisation, Heather M Wallace; funding acquisition, Heather M Wallace; investigation, Misael Corral; methodology, Misael Corral and Heather M Wallace; resources, H.M.W.; supervision, H.M.W.; validation, M.C.; visualisation, M.C.; writing—original draft, M.C.; writing—review and editing, H.M.W.. All authors have read and agreed to the published version of the manuscript. ",

N1 - Funding: M.C. was funded by CONACyT, Mexico with the PhD scholarship 237771/411030. Acknowledgments: We would like to thank Mark Burns of Aminex Therapeutics for kindly providing the
AMXT compounds and P.M. Woster from Medical University of South Carolina for DFMO and Gary Cameron for LC-MS analyes
Author Contributions: M.C. and H.M.W. designed the study. M.C. performed the experiments, interpreted the data and wrote the manuscript. H.M.W. interpreted the data and revised the manuscript. Conceptualisation, Heather M Wallace; funding acquisition, Heather M Wallace; investigation, Misael Corral; methodology, Misael Corral and Heather M Wallace; resources, H.M.W.; supervision, H.M.W.; validation, M.C.; visualisation, M.C.;
writing—original draft, M.C.; writing—review and editing, H.M.W.. All authors have read and agreed to the published version of the manuscript.

PY - 2020/4

Y1 - 2020/4

N2 - Polyamines are essential growth factors that have a positive role in cancer cell growth. Their metabolic pathway and the diverse enzymes involved have been studied in depth in multiple organisms and cells. Polyamine transport also contributes to the intracellular polyamine content but this is less well-studied in mammalian cells. As the polyamine transporters could provide a means of selective drug delivery to cancer cells, a greater understanding of polyamine transport and its regulation is needed. In this study, transport of polyamines and polyamine content was measured and the effect of modulating each was determined in human colorectal cancer cells. The results provide evidence that upregulation of polyamine transport depends on polyamine depletion and on the rate of cell growth. Polyamine transport occurred in all colorectal cancer cell lines tested but to varying extents. The cell lines with the lowest basal uptake showed the greatest increase in response to polyamine depletion. Kinetic parameters for putrescine and spermidine suggest the existence of two separate transporters. Transport was shown to be a saturable but non-polarised process that can be regulated both positively and negatively. Using the polyamine transporter to deliver anticancer drugs more selectively is now a reality, and the ability to manipulate the polyamine transport process increases the possibility of using these transporters therapeutically.

AB - Polyamines are essential growth factors that have a positive role in cancer cell growth. Their metabolic pathway and the diverse enzymes involved have been studied in depth in multiple organisms and cells. Polyamine transport also contributes to the intracellular polyamine content but this is less well-studied in mammalian cells. As the polyamine transporters could provide a means of selective drug delivery to cancer cells, a greater understanding of polyamine transport and its regulation is needed. In this study, transport of polyamines and polyamine content was measured and the effect of modulating each was determined in human colorectal cancer cells. The results provide evidence that upregulation of polyamine transport depends on polyamine depletion and on the rate of cell growth. Polyamine transport occurred in all colorectal cancer cell lines tested but to varying extents. The cell lines with the lowest basal uptake showed the greatest increase in response to polyamine depletion. Kinetic parameters for putrescine and spermidine suggest the existence of two separate transporters. Transport was shown to be a saturable but non-polarised process that can be regulated both positively and negatively. Using the polyamine transporter to deliver anticancer drugs more selectively is now a reality, and the ability to manipulate the polyamine transport process increases the possibility of using these transporters therapeutically.

KW - polyamines

KW - putrescine

KW - spermidine

KW - uptake

KW - DFMO

KW - transport

KW - drug delivery

KW - colorectal cancer

U2 - 10.3390/biom10040499

DO - 10.3390/biom10040499

M3 - Article

C2 - 32218236

VL - 10

JO - Biomolecules

JF - Biomolecules

SN - 2218-273X

IS - 4

M1 - 499

ER -

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